During the past year, there have been two areas of research ongoing in the Molecular Immunology Section: 1) identification of structure/function relationships of human CD8+ T cell antigen-specific receptors (TCR) and 2) determination of differential gene expression in CNS lesions of MS patients. Structural analysis of TCR recognition has been examined using T cell assays, kinetic and thermodynamic binding assays, and X-ray crystallography. The emphasis on these studies has been on the mechanism of HTLV-I Tax peptide-specific TCRs recognition of MHC HLA-A2. The overall conclusion is that there is a location on the central portion of the alpha one helix of HLA-A2 that provides interactions crucial to TCR functional recognition of HLA-A2. Analysis of differential gene overexpression in CNS lesions of MS patients and the brains of mice with EAE by cDNA microarray technology has been performed by monitoring the expression pattern of over 2800 genes known or suspected to be involved in immune responses. Four genes were found to be overexpressed in each of 18 MS lesions examined and in the brains of two strains of mice with EAE compared to normal white mattter. The product of one of these genes, 5-Lipoxygenase (5-LO), was found in the lesions of four different MS patients but not in normal white matter by immunohistochemistry. Since 5-LO is the enzyme crucial for the biosynthesis of inflammatory leukotrienes, this previously unreported proinflammatory enzyme in MS lesions may contribute to pathology, and provide a new opportunity for therapeutic intervention. Thus, cDNA microarray technology represents a powerful new tool for the identification of genes not previously associated with the MS disease process.
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